A minimal human MBP promoter-lacZ transgene is appropriately regulated in developing brain and after optic enucleation, but not in shiverer mutant mice.
Previous studies, both in vitro and in vivo, suggest that small portions of the mouse myelin basic protein (MBP) promoter are sufficient to activate regulated expression of MBP. To confirm our previous in vitro studies, we prepared transgenic mice with short regions of the human MBP promoter fused to the lacZ reporter gene. We found that 750 nucleotides of the proximal human MBP promoter is sufficient to activate oligodendrocyte-specific, developmentally regulated expression of lacZ in three independent lines. This promoter, however, does not activate expression of lacZ in Schwann cells in peripheral nerve or in adult mouse brain. The relative levels of beta-galactosidase specific activity, mRNA, and transcription parallel those of MBP mRNA during myelinogenesis. Thus, we exploited this transgene as a quantitative tool to evaluate the response to stimuli known to affect myelination. Transgene expression is reduced 75 % after optic enucleation, as previously reported for levels of MBP mRNA, indicating that axons signal to this portion of the proximal MBP promoter to fully activate MBP expression during myelinogenesis. Instead, in adult shiverer mice, another setting in which MBP transcription is modulated, transgene expression is not increased, in contrast to the increased transcriptional activation of MBP previously reported in these mice. These data suggest that the regulatory region that mediates transcriptional activation of the MBP gene is modular, since discrete subregions are required for activation in Schwann cells, during myelinogenesis in oligodendrocytes, during maintenance myelination in adult brain, and in the dysmyelinating mutant shiverer mouse.
Wrabetz
L
L
DIBIT and Department of Neurology, San Raffaele Scientific Institute, Milano, Italy. wrabetl@dibit.hsr.it
Taveggia
C
C
Feltri
M L
ML
Quattrini
A
A
Awatramani
R
R
Scherer
S S
SS
Messing
A
A
Kamholz
J
J
D000818:Animals; D001369:Axons / Q000502:physiology; D003711:Demyelinating Diseases / Q000235:genetics*; D015353:Eye Enucleation; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007763:Lac Operon; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics*; D009836:Oligodendroglia / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012583:Schwann Cells / Q000378:metabolism
D004676:Myelin Basic Protein